Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes

Abstract

Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.

Keywords: Acute Erythroid Leukemia; Acute Myeloid Leukemia; hematopoietic disorders; myeloid neoplasms.

Figure 1

Mechanisms implicated in the pathobiology of AEL. (A) EPOR activation and subsequent constitutional activation of the downstream signaling effectors, such as signal transcription activators (STATs), PI3K/AKT, and mitogen-activated protein (MAP) or extracellular signal-regulated (ERK) kinases, promote the development of proerythroblasts. (B) Reduced GATA1 expression, as well as the ectopic expression of GATA1 interactors/transcriptional complexes (ERG, ETO2, SKI, and SPI1), results in the inhibition of normal erythroid differentiation. An aberrant overexpression of CDX4, a developmental regulator, mediates leukemogenesis. (C) Overexpression of a proto-oncogene, c-MYC, also halts erythroid differentiation. (D) TP53 mutations promote the proliferation and survival of hematopoietic stem cells and progenitor cells, accumulating additional DNA damage. (E) Activating mutations in GATA2 and C/EBPα, enhancing both erythroid genes expression and chromatin accessibility. (F) Epigenetic dysregulation (inactivating mutations of TET2 and DNMT3A/B) promote hematopoietic stem cell renewal and inhibit differentiation. Created with BioRender.com.